Institute: University of Sheffield
Investigating the host senescence responses triggered by the typhoid toxin during acute enteric fever
Salmonella Typhi bacteria can invade the intestines and blood and lead to a disease called typhoid fever. Despite vaccines and improved sanitation, the disease still affects around 11 million people each year worldwide and results in nearly 130,000 deaths, predominantly in low and middle income countries (LMICs).
One of the big challenges for reducing Salmonella Typhi infection rates is the group of people who don’t completely clear the bacteria from their system after the initial infection. They continue to carry the bacteria long-term in their intestines without symptoms. These ‘chronic carriers’ spread the bacteria to other people, perpetuating the disease – yet scientists don’t yet understand what factors lead to this condition.
We have recently discovered more about a link between chronic carriage and a toxin made by the bacteria (called typhoid toxin). Our results show that intestinal cells exposed to the toxin suffer DNA damage, and respond by releasing proteins that put their neighbours into a zombie-like state called senescence. This leaves the cells more vulnerable to bacterial invasion, and could be the way in which Salmonella Typhi establishes a chronic infection.
In this project we are going to analyse samples previously collected from a human infection study run at Oxford Vaccine Group, during which volunteers were exposed to either natural Salmonella Typhi, or Salmonella Typhi genetically modified so it can’t make typhoid toxin. We aim to find signatures of proteins released in response to the toxin and evidence that cells are entering the zombie-like senescent state as a result.
More about Dr Humphreys here.